Abstract 2290: Crosstalk between ER and PI3K signaling pathways in human luminal type breast cancer and its therapeutic implications

Autor: Martin Shea, Ryan M. Gillihan, Chad J. Creighton, Adrian V. Lee, Rachel Schiff, Kent Osborne, Susan G. Hilsenbeck, Xiaoyong Fu, Sarmistha Nanda
Rok vydání: 2011
Předmět:
Zdroj: Cancer Research. 71:2290-2290
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2011-2290
Popis: Background: We have recently shown that the luminal B subtype breast cancer (BC) is associated with PI3K molecular signature. Breast tumors of the luminal B subtype generally have lower ER expression levels and/or activity and are more aggressive and less sensitive to endocrine therapy when compared to the luminal A tumors. To further investigate the role of PI3K signaling in BC luminal types and endocrine resistance, we have characterized an array of luminal A and B cell lines, as well as their endocrine resistant derivatives, to examine how modulation of the PI3K pathway can influence ER activity and endocrine sensitivity. Materials and Methods: We focused on endocrine resistant derivatives of two luminal A (ZR75-1 and BT483) and two luminal B (ZR75-B and CAMA-1) cell lines. Resistant clones were developed by long-term (>6 months) endocrine treatment [estrogen deprivation (ED) or ED plus Tamoxifen (Tam)]. IC50 values of the PI3K inhibitor BEZ-235 were determined in the parental and the endocrine resistant lines, and qRT-PCR was performed to measure the effect of the inhibitor on mRNA levels of ER and its regulated genes (e.g. PR, CAV1, IGF1R and IRS1). Cells were also treated (4 days) with Tam, BEZ-235, or the combination and growth inhibition assays were conducted to assess the drugs efficacy. Inducible PTEN knockdown clones were established in MCF7L and BT483 cell lines. Endocrine sensitivity of these clones was studied in vitro and in vivo, using xenograft mouse models. Results: Ten days of treatment showed that all parental lines were sensitive to endocrine therapy. In contrast, stabilized endocrine resistant cell lines showed similar cell growth rate under Tam or ED treatment compared to control E2 treatment (p>0.05). ZR75-1 endocrine resistant derivatives acquired higher sensitivity to BEZ-235 treatment compared to the parental (p Discussion: The inverse association between PI3K and ER pathways in luminal BC cell lines validates the relevance of these models for further studies. Endocrine resistant phenotype may be partially caused by activated PI3K signaling. Our data suggest that inhibition of PI3K signaling can restore ER levels and/or activity, thereby reversing the aggressive and hormonal-refractory phenotype of the tumors, and achieving improved endocrine therapy response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2290. doi:10.1158/1538-7445.AM2011-2290
Databáze: OpenAIRE